Category: CRISPR

Shortly after I finished reading Jennifer Doudna and Samuel Sternberg’s book on the development of the CRISPR gene editing technology, CRISPR was leading the news headlines. Shoukhrat Mitalipov and his international team announced their successful and efficient correction of a mutant MYBPC3 gene which causes the condition hypertropic cardiomyopathy, the cause of many of the sudden heart attacks in young people, in non-viable human embryos. Though it took some time for the news stories to use the word “CRISPR”, as it is not yet a household name, the news sparked many opinion pieces warning of a slippery slop, down which we will be lead to “designer babies”. But these are the same arguments we have been having since the dawn of the recombinant DNA era in the 1970s, with little reconsideration in light of the actual facts of how the technology and the human genome works. What I found lacking in these analyses was a thorough understanding of the actual scope and limits of CRISPR gene editing technology. Gladly, A Crack in Creation offers such a nuanced background straight from those deeply embedded in the science; Jennifer Doudna is one of the scientists leading the development of CRISPR gene editing and Samuel Sternberg started his career as Doudna’s doctoral student.

The acronym CRISPR stands for the cumbersome phrase “Clustered Regularly Interspaced Short Palindromic Repeats”. This refers to clustered stretches of base pairs in the genome of bacteria which are the same backwards as they are forwards, with non-repetitive “spacers” between them. Bacteria don’t tend to have superfluous parts to their genome, so researchers before Doudna were prompted to investigate their function. The spacer sequences were found to be derived from viral DNA, and the CRISPR sequences were found to be associated with the Cas proteins, which can cut DNA. With this information, the mechanism was pieced together. When the bacterium is infected with a virus, the cell copies this DNA and inserts it between the palindromic repeats. This acts as a cellular “memory”, so that when the same strain of virus infects the cell, it can transcribe into RNA the “memorised” sequence and use the RNA fragments to guide the Cas9 protein to the viral DNA. Cas9 then cuts the DNA with the characteristic double-strand cut. This allows bacteria to have something like the mammalian innate immune system, but unlike the immune system, CRISPR “immunity” involves infection leading to changes in DNA. This opens up the potential for this system of DNA editing, honed by evolution, to be adapted for human ends.

Doudna and Sternberg place CRISPR in the context of previous gene editing technologies, such as TALENs and zinc finger nucleases, which acted in a similar way to the CRISPR system, and the long history of largely unsuccessful gene therapies. This gives the reader the proper context of gene editing as not a quantum leap but a progression from cruder technologies. CRISPR seems startling only because we are now drawing on nature’s more efficient solutions rather than the fumbling designs of the human hand.

Jennifer Doudna was at the forefront of CRISPR emergence from obscure microbial trick to a potentially powerful tool. She and her colleagues modified Cas9 and produced a simpler guide RNA, allowing CRISPR to be used to alter the DNA of all organisms in which it has been attempted. Alongside their work, Doudna and Sternberg also stepped out from the shadows of academia and onto the public stage. These years of public engagement and consultation with policy makers have allowed Doudna and Sternberg to hone their explanations of the science and to explore the implication with skill, the great strength of the book.

Their main ethical concerns with CRISPR are in regards to its use in germ cells and embryos, as this would alter the genetic constitution of the person and their descendants permanently. Doudna and Sternberg don’t call for rigid ban on this editing in all cases, but would rather scientists refrain from implementing this until the safety and efficacy concerns are addressed and there has been a public conversation on whether we should alter the future of humanity in this manner. Instead, Doudna and Sternberg champion the therapeutic use of CRISPR by editing the DNA of somatic cells. This only alters the DNA of the organ or area treated in the patient, and cannot affect their offspring, and could potential eradicate HIV, hemophilia and similar diseases.

Doudna and Sternbrg do stress throughout the book that the technology is currently imprecise and produces a mosaic of altered and unaffected cells in treated tissues. However, the work done by Mitalipov et al and others show that these challenges are being rapidly overcome. The authors’ reliance on the current inefficiencies of CRISPR technologies to suggesting that it will not be the path to designer babies does lack persuasive power. For the non-specialists seeing seemingly miraculous developments emerge every month now, technical barriers seem only temporary, until the next bit of lab-based magic happens. They give little consideration to the main concerns of those predicting a eugenic future, not just that the genes of embryos may be edited but that they will be altered so as to produce a monoculture of blue-eyed Übermensch. This is unlikely to happen not necessarily due to technological limits, but most importantly due to the extreme ambiguity of human development and gene expression. There is no gene for musical virtuosity, and even a relatively simple trait like eye colour is determined and influence by a myriad of different genetic pathways, perturbations in any of which may or may not alter the outcome. And then there are the environmental influences which can make the difference between the virtuoso and the tone-deaf.

For all of these reasons, gene editing will have a limited impact on the complex traits that cause middle-class parents so much anxiety, but it could have a significant impact on the incidence of traits and diseases with simple or Mendelian genetic causes. CRISPR could never bring about the Übermensch, but if germ cell and embryonic editing occurs, if only in China, for example as there is already the desire to do so, then diseases like Huntington’s, but also deafness and some learning disabilities, could begin to disappear from the population. CRISPR gene editing of embryos poses questions regarding the diversity of the human gene pool, whether we can propose to alter it, and if so, what of the limited amount of diversity we can affect do we want to alter?

Stylistically, the book is written in Doudna’s voice, but I gather it was Sternberg’s idea to write it. This gives the work some anchoring in the life of human beings, conveying the collaborative nature of the field as well as the human frailties that lie behind the top-tier publications. The book opens with Doudna’s anxiety dream of being subsumed by a wave, which she suggests symbolises her being overwhelmed by the enormous ethical implications of her work. Later, they recount a far more unsubtle dream in which a pig-faced Hitler asks Doudna to explain the CRISPR technology to him, which needs no explanation. This gives the book an accessible moral sensibility, the ethics are not discussed entirely dispassionately and academically, but from the viewpoint of someone who do not want their work to be used for evil. But the personal slant is limited and Doudna’s emotional responses feel mediated as the book is co-authored, and so lose some of their power. I would have liked to have seen more of the mind of the scientist at work, to understand a real-life Victor Frankenstein, though given how soon after the introduction of CRISPR gene editing the book was written, the first Doudna et al. CRISPR paper was only published in 2012, it is too early to expect a tell-all memoir like Watson’s The Double Helix.

On the whole, A Crack in Creation is a very clear explanation of the science and considered and non-diadactic exploration of associated ethical concerns, inviting the reader to stop and consider the implications in an informed manner rather than being swept up in an ill-informed media furor. And at the very least, it will provide a wealth of material fro Doudna to draw upon when she makes her no-doubt forthcoming Nobel Prize acceptance speech.